Abstract

In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Despite the inefficiency of ATP generation through glycolysis, the breakdown of glucose into lactate provides cancer cells with a number of advantages, including the ability to withstand fluctuations in oxygen levels, and the production of intermediates that serve as building blocks to support rapid proliferation. Recent evidence from many cancer types supports the notion that pervasive metabolic reprogramming in cancer and stromal cells is a crucial feature of neoplastic transformation. Two key transcription factors that play major roles in this metabolic reprogramming are hypoxia inducible factor-1 (HIF1) and MYC. Sirtuin-family deacetylases regulate diverse biological processes, including many aspects of tumor biology. Recently, the sirtuin SIRT6 has been shown to inhibit the transcriptional output of both HIF1 and MYC, and to function as a tumor suppressor. In this Review, we highlight the importance of HIF1 and MYC in regulating tumor metabolism and their regulation by sirtuins, with a main focus on SIRT6.

SIRT6: a multi-functional enzyme implicated in diverse pathologies

The sirtuins are a conserved family of NAD+-dependent enzymes that regulate many cellular functions, in particular those related to stress responses. The SIR2 (silent information regulator 2) gene in budding yeast was the first sirtuin to be identified and functionally characterized. The initial interest in sirtuins was related to their roles in regulating lifespan. Several groups reported that an increased dosage of SIR2 and its homologs promotes increased lifespan in budding yeast, worms and flies (Hoffmann et al., 2013; Mouchiroud et al., 2013; Stumpferl et al., 2012; Viswanathan and Guarente, 2011). As an aside, it is should be noted that one prominent study did not reproduce these pro-longevity effects of sirtuins in worms or flies (Burnett et al., 2011), and aspects of the roles of sirtuins in yeast longevity are also still hotly debated (Longo and Kennedy, 2006). The discrepant results obtained by different laboratories likely result from variations in experimental protocols, strain backgrounds and/or husbandry conditions. Notwithstanding these controversies, the apparently conserved pro-longevity effects of invertebrate sirtuins have led to intensive efforts to characterize the functions of the seven mammalian sirtuins, termed SIRT1-SIRT7.

In agreement with the results from invertebrate models, it is now known that at least two mammalian sirtuins, SIRT1 and SIRT6, extend lifespan in mice when overexpressed. In the case of SIRT1, brain-specific, but not whole-body, overexpression increases lifespan through increased neural activity in hypothalamic nuclei, leading to improved maintenance of skeletal muscle mitochondrial function and other beneficial effects (Herranz et al., 2010; Satoh et al., 2013). Whole-body SIRT6 overexpression extends lifespan in male mice specifically by attenuating insulin–IGF-1-like signaling (IIS), and potentially by decreasing the incidence of lung carcinoma (Kanfi et al., 2012; Lombard and Miller, 2012).

In line with the putative role of sirtuins in promoting longevity, a large body of evidence has revealed major roles for individual sirtuins in suppressing diverse age-associated pathologies, including cancer and metabolic diseases (Giblin et al., 2014). The primary focus of this Review is the sirtuin SIRT6, and specifically its roles in neoplastic transformation, an area in which there has been a large amount of recent progress, as discussed in depth in the following sections. Molecularly, a major function of SIRT6 is to deacetylate histone H3 acK9 and acK56 (Kawahara et al., 2009; Michishita et al., 2008; Michishita et al., 2009; Yang et al., 2009). In addition to its lysine deacetylase activity, SIRT6 can act as a mono-ADP ribosyltransferase towards PARP-1, and a TNFα deacylase (Jiang et al., 2013; Pan et al., 2011). Binding of free fatty acids to SIRT6 enhances its deacetylase activity in vitro (Feldman et al., 2013), although the in vivo significance of this finding remains to be established. Through its H3 deacetylase activity, SIRT6 attenuates the transcriptional activity of numerous transcription factors – NF-κB, HIF1, MYC (c-MYC) and JUN – to inhibit target gene expression (Kawahara et al., 2009; Sebastián et al., 2012; Sundaresan et al., 2012; Xiao et al., 2012; Zhong et al., 2010). Likewise, SIRT6 suppresses the activities of the lipogenic transcription factors SREBP1 and SREBP2 through multiple mechanisms (Elhanati et al., 2013; Tao et al., 2013).

SIRT6 in cancer

The finding that SIRT6 functions in regulating metabolism, genomic stability and cellular senescence – all phenomena relevant for neoplasia – has prompted multiple groups to assess roles for SIRT6 in cancer. Collectively, these studies have shown that SIRT6 plays both oncogenic and tumor suppressor roles, in a cell- and context-specific manner (Fig. 1). Increased SIRT6 expression has been reported in pancreatic, prostate and breast cancers, where high SIRT6 levels are associated with chemotherapy resistance and poor prognosis (Bauer et al., 2012; Khongkow et al., 2013; Liu et al., 2013b). In this context, high levels of SIRT6 promote deacetylation and inactivation of the tumor suppressor proteins FOXO3a and p53, and, in addition, activate production of the pro-inflammatory cytokines TNF and IL-8, in part through the Ca2+ channel TRPM2 (Bauer et al., 2012).

Dual roles for SIRT6 in cancer. SIRT6 has been reported to have both tumor suppressor and oncogenic properties. Reduced levels of SIRT6 have been described in colon cancer (CC), hepatocellular carcinoma (HCC), pancreatic cancer (PaC) and head and neck squamous cell carcinoma (HNSCC), correlating with increased cancer stage and grade, and/or with a shortened time to relapse in comparison to tumors with higher levels of SIRT6. SIRT6 can protect against tumorigenesis through multiple pathways: (1) inhibition of HIF-1α and MYC transcriptional activity, which decreases glycolysis and cellular proliferation, respectively; (2) inhibition of the anti-apoptotic factor survivin; (3) activation of the p53 and p73 apoptosis pathways in cancer cells specifically. Furthermore, SIRT6 represses SREBP1 and SREBP2 (SREBP1/2) and JUN activity, resulting in reduced lipogenesis and insulin–IGF-1-like signaling (IIS), respectively. Both of these processes likely impact cancer cell proliferation. By contrast, high SIRT6 levels have been reported in breast cancer (BC), PaC and prostate cancer (PrC), and are associated with drug resistance and poor prognosis. High SIRT6 levels promote cellular proliferation through deacetylation of the cell cycle control proteins FOXO3a and p53, and increase IL-8- and TNF-mediated inflammatory responses, angiogenesis and tumor metastasis in part through activation of the Ca2+ channel TRPM2. Ac, acetyl group; TNF, tumor necrosis factor; IL-8, interleukin-8.

Warburg effect

Cells regulate glucose metabolism based on their differentiation status and growth state, and the availability of oxygen. Glycolysis is the metabolic process in which glucose is converted into pyruvate. In differentiated tissues, when oxygen is present, pyruvate then enters the mitochondrial tricarboxylic acid (TCA) cycle to be fully oxidized to CO2 (oxidative phosphorylation). However, under hypoxic conditions, pyruvate is instead converted into lactate in anaerobic glycolysis (Vander Heiden et al., 2009).

It might at first seem surprising that cancer cells carry out a form of metabolism that is relatively inefficient at generating ATP. For each molecule of glucose that enters the cell, oxidative phosphorylation generates up to roughly 36 molecules of ATP, whereas aerobic glycolysis provides only two net ATP molecules (Vander Heiden et al., 2009). Thus, glycolysis must provide rapidly proliferating cells with benefits that outweigh a lower efficiency of ATP production. A large body of recent work indicates that glycolysis and lactate production provide cancer cells with a number of advantages that drive tumorigenesis. First, in the presence of ample glucose, glycolysis generates ATP more rapidly than oxidative phosphorylation (Wu and Zhao, 2013). Second, aerobic glycolysis provides the cell with an increased capacity to generate precursors for synthesis of macromolecules (lipids, nucleic acids and proteins) that are essential for rapid cell division (Soga, 2013; Vander Heiden et al., 2009; Wu and Zhao, 2013). Finally, lactate secretion by tumors creates a toxic environment for immune cells, thereby inhibiting immune surveillance, and stimulates endothelial cells to form new blood vessels, facilitating tumor metastasis (Hirschhaeuser et al., 2011). Lactate levels are negatively correlated with survival in patients with diverse tumor types, including cervical cancer, head and neck squamous cell carcinoma, and glioblastoma multiforme (Hirschhaeuser et al., 2011). In addition, high blood lactate levels are associated with tumor radioresistance (Hirschhaeuser et al., 2011). It is now known that aerobic glycolysis is a part of the broader metabolic reprogramming that occurs in cancer cells (Ward and Thompson, 2012).

Highlighting the central role of metabolic reprogramming in neoplasia, mutations in genes that encode proteins involved in mitochondrial metabolism can promote tumorigenesis (Wu and Zhao, 2013). A number of transcription factors have been identified as drivers of cancer metabolism (Soga, 2013; Ward and Thompson, 2012). In this Review we will focus on two such transcription factors – HIF-1α and MYC – that have been linked to SIRT6 (Sebastián et al., 2012). Furthermore, we will discuss the roles of other sirtuin family members in modulating HIF-1α and MYC activity. Understanding the mechanistic interplay between sirtuin proteins and these transcription factors might uncover vulnerabilities in cancer cells that could be targeted in the context of novel anti-neoplastic therapies.

HIF1 is a driver of metabolic reprogramming in cancer

Hypoxia-inducible factor

The hypoxia-inducible factors (HIFs) – HIF1, HIF2 and HIF3 – are transcription factors that drive glycolysis and lactate production when the oxygen supply is limited. HIFs consist of an α-subunit, levels of which are sensitive to oxygen concentration, and a stable β-subunit. Under physiological oxygen tension, the α-subunit undergoes hydroxylation by prolyl hydroxylase (PHD) and subsequent proteasomal degradation mediated by von Hippel-Lindau (VHL) protein and E3-ligase (Keith et al., 2012; Semenza, 2010). However, hypoxia or mitochondrial reactive oxygen species (ROS) inhibit the activity of PHD, stabilizing the α-subunit of HIF and resulting in the HIF complex binding to hypoxia-responsive elements (HREs) in the promoters of HIF target genes. The ubiquitously expressed HIF-1α was first identified in 1995, followed shortly after by the discovery of HIF-2α (Ema et al., 1997; Flamme et al., 1997; Hogenesch et al., 1997; Tian et al., 1997; Wang et al., 1995). HIF-2α was initially thought to be mainly expressed in endothelial cells; however, expression of HIF-1α and HIF-2α overlaps in many cell types, and they regulate common as well as unique target genes (Hu et al., 2003; Keith et al., 2012; Raval et al., 2005; Wiesener et al., 2003).

HIF1 induces expression of a number of glycolytic genes, such as SLC2A1 and SLC2A3, hexokinases 1 and 2, LDHA, MCT4 and PDK1. SLC2A1 and SLC2A3 encode the glucose transporters GLUT1 and GLUT3, respectively, which are responsible for basal, non-insulin-responsive glucose uptake. Once imported into the cell, glucose is converted to glucose-6-phosphate in the initial step of glycolysis by hexokinases. Pyruvate generated in the final step of glycolysis can either be converted into acetyl-CoA by pyruvate dehydrogenase (PDC) for further metabolism in the TCA cycle, or be converted into lactate. Under hypoxic conditions, HIF1 upregulates expression of glycolytic enzymes and favors lactate production, while inhibiting pyruvate entry into the TCA cycle. Two of HIF1’s major transcriptional targets are pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase (LDH). PDK1 phosphorylates the E1α subunit of PDC, thereby inhibiting holoenzyme activity. LDH catalyzes conversion of pyruvate into lactate. Once formed, lactate is transported out of the cell by the monocarboxylate transporter MCT4 (Keith et al., 2012; Semenza, 2010). Increased expression of HIF-1α and HIF-2α has been detected in many different cancer types as well as in tumor-associated stromal cells, and, in both cases, high HIF levels are associated with a poor clinical outcome (Bonuccelli et al., 2010; Keith et al., 2012; Pavlides et al., 2010; Semenza, 2010).

The finding that increased HIF expression has been observed in both cancer cells as well their associated stromal cells supports the existence of the ‘reverse Warburg effect’. According to this model, stromal cells rather than the cancer cells are reprogrammed to perform aerobic glycolysis in many tumors. Hence, stromal cells generate lactate, ketone bodies and other energy-rich intermediates that can be taken up by neighboring cancer cells to fuel oxidative phosphorylation and mitochondrial metabolism (Martinez-Outschoorn et al., 2012; Sotgia et al., 2012). Unfortunately, little characterization of the roles for sirtuins in tumor stromal cells has been performed to date. Such studies would entail an examination of the properties of sirtuin-proficient tumor allografts implanted into sirtuin-deficient animals, and/or ablation of sirtuin genes specifically in stromal cells. Although potentially providing important new insights, such studies have not yet been described in the literature. Therefore, we focus our discussion on roles for sirtuins in neoplastic cells themselves.

Consistent with a tumor suppressor function of SIRT3 in humans, SIRT3 mRNA and protein levels are decreased in a large fraction of human breast cancers and other human malignancies, associated with deletion of the SIRT3 gene locus (Finley et al., 2011; Kim et al., 2010a). However, it should be pointed out that recent work links an extra copy of the SIRT3 gene with a tumor-prone phenotype in humans (Aury-Landas et al., 2013). Overall, current evidence suggests that, by maintaining low cellular ROS levels, SIRT3 inhibits glycolytic metabolism, and suppresses tumor development and progression.

Finally, the nuclear sirtuin SIRT7 has recently been reported to regulate HIF1. SIRT7 binds both HIF-1α and HIF-2α, reducing their stability and consequently their transcriptional activity. It is unknown how SIRT7 regulates HIF protein stability; this effect occurs independently of SIRT7 deacetylase activity, and SIRT7 does not regulate known HIF-1α degradation pathways (Hubbi et al., 2013). Whether SIRT7 plays a role in HIF-1α-mediated glycolysis during tumorigenesis remains to be elucidated. SIRT7 promotes malignant properties of tumor cells by deacetylating histone H3 at lysine 18 (Barber et al., 2012).

Oncogenic MYC regulates biomass production in cancer

The MYC oncogene

MYC, L-MYC (MYCL) and N-MYC (MYCN) are the three members of the oncogenic MYC transcription factor family. N-MYC and MYC possess overlapping functions, although expression of N-MYC is more restricted, being most abundant in developing brain and kidney, as well as in post-mitotic cells undergoing differentiation (Dang, 2012; Hirvonen et al., 1990; Malynn et al., 2000). MYC (c-MYC) heterodimerizes with its partner protein MAX (MYC-associated factor X) to bind specific DNA sequences, termed E-boxes, found in promoter regions of 30% of all genes (Dang et al., 2009). In this regard, recent data indicate that MYC functions as an amplifier of the expression of essentially all expressed genes, in a cell-type-specific manner (Lin et al., 2012; Nie et al., 2012). To regulate gene expression, the MYC-MAX complex requires interaction with other transcription factors such as E2F1 and HIF1. MYC positively regulates ribosomal biogenesis, glucose metabolism, and mitochondrial respiration in most cell types (Dang et al., 2009). Ribosomal genes are particularly important MYC targets in the context of cellular transformation; heterozygosity for a ribosomal gene (L24) is sufficient to attenuate MYC-driven oncogenesis in B-cells (Barna et al., 2008).

With respect to glucose metabolism and mitochondrial function, a complex interplay exists between MYC and the HIF proteins. Under hypoxic conditions, HIF1 inhibits MYC activity, either through interruption of MYC-MAX binding or through stimulation of proteasomal degradation of MYC (Corn et al., 2005; Gordan et al., 2007b). However, oxygen levels tend to fluctuate in tumors (Dewhirst, 2007). Therefore, in tumor cells, where MYC levels are generally elevated, HIF-1α will only inhibit MYC activity during short periods of severe hypoxia, whereas, at other times, the high MYC levels can drive cellular proliferation (Gordan et al., 2007b). In contrast to HIF1, HIF2 was reported to promote MYC-MAX heterodimerization under hypoxic conditions and enhance MYC activity (Gordan et al., 2007a). Because HIF2 is expressed in endothelial cells, it has been postulated that, via this mechanism, HIF2 stimulates endothelial proliferation and angiogenesis. However, endothelial-specific deletion of HIF-2α does not affect endothelial proliferation per se; instead, it results in defective tumor vessel formation and increased tumor hypoxia and apoptosis (Skuli et al., 2009).

Increased MYC activity is a feature of many diverse human tumors (Dang et al., 2008; Dang et al., 2009). A key function of MYC in cancers is regulating the absorption and metabolism of the non-essential amino acid glutamine. In 1955, Harry Eagle observed that cellular proliferation of normal and malignant cells in culture requires exogenous glutamine (Eagle, 1955). Glutamine uptake by cancer cells exceeds that of any other amino acid by tenfold, and glutamine deprivation of transformed cells induces apoptosis (Wise et al., 2008; Yuneva et al., 2007). The importance of glutamine in cancer cell survival and growth is due largely to its involvement in macromolecular synthesis (Dang, 2010; Wise and Thompson, 2010). Glutamine is essential for protein translation in cancer cells. When glutamine is imported into the cell via the amino acid transporter SLC1A5 (also known as ASCT2), a portion of it is exported out of the cell via the bidirectional amino acid transporter SLC7A5, concomitant with uptake of extracellular essential amino acids (EAAs). Intracellular EAAs activate mTORC1, a master regulator of protein translation (Wise and Thompson, 2010). In addition, glutamine and glucose are key nitrogen and carbon sources for synthesis of all non-essential amino acids except tyrosine (Wise and Thompson, 2010).

Glutamine can enter the TCA cycle via conversion to glutamate and subsequently to α-ketoglutarate (α-KG). A large fraction of α-KG is further converted to malate, pyruvate and subsequently lactate, which is secreted by the cell. As a by-product of the conversion of malate into pyruvate by malate dehydrogenase, NADP+ is converted into NADPH. Hence, glutamine metabolism generates a substantial fraction of the NADPH that is essential for nucleotide and lipid synthesis, and cellular proliferation (DeBerardinis et al., 2007; Vander Heiden et al., 2009). Furthermore, the cancer cell generates mitochondrial oxaloacetic acid (OAA) from glutamine metabolism (DeBerardinis et al., 2007). OAA and acetyl-CoA condense to form citrate, which is exported from mitochondria into the cytosol. Here, citrate can liberate acetyl-CoA for lipid synthesis, whereas the remaining OAA is converted to pyruvate (Wise and Thompson, 2010). Through these processes, glutamine acts as an important substrate for energy production (DeBerardinis et al., 2007), as a carbon and nitrogen source to support protein, nucleotide and lipid synthesis (Jones and Thompson, 2009; Wise and Thompson, 2010), and as a means to generate NADPH (Wise and Thompson, 2010). Recent studies have revealed that, in cancer cells with impaired mitochondrial function, or under hypoxic or pseudo-hypoxic conditions, glutamine is converted to α-KG and then to citrate via reductive carboxylation, which is subsequently employed as a precursor for lipid synthesis and to replenish TCA cycle intermediates (Metallo et al., 2012; Mullen et al., 2012).

In addition to MYC, SIRT1 also forms a positive feedback loop with N-MYC, whereby N-MYC enhances SIRT1 expression and SIRT1 inhibits N-MYC proteasomal degradation by promoting N-MYC phosphorylation (through MKP3, which dephosphorylates and inactivates ERK) (Marshall et al., 2011). It is currently unknown whether SIRT1 regulates the metabolic effects of MYC in cancer; however, based on these findings, it is likely that SIRT1 can induce expression of MYC target genes important in mediating metabolic reprogramming. Indeed, two reports demonstrated that SIRT1 stimulates MYC-induced LDHA expression (Mao et al., 2011; Vettraino et al., 2013).

The MYC oncoproteins also form a positive feedback loop with SIRT2. MYC and N-MYC upregulate SIRT2 expression, and SIRT2 inhibits the ubiquitylation and degradation of both of these MYC proteins by suppressing expression of NEDD4, an E3 ubiquitin-protein ligase (Liu et al., 2013a). By promoting MYC protein stabilization, SIRT2 can enhance growth of neuroblastoma and pancreatic cancer cells (Liu et al., 2013a). Importantly, however, other studies point to roles for SIRT2 in tumor suppression via maintenance of genomic stability (Kim et al., 2011).

Recently, SIRT7 was identified as another suppressor of MYC function. In response to endoplasmic reticulum (ER) stress, XBP1, a regulator of the unfolded protein response (UPR), binds to the SIRT7 promoter to induce transcription. SIRT7 in turn is recruited by MYC to block MYC-mediated transcription of ribosomal genes, to inhibit cellular protein translation. Suppression of ribosomal biogenesis by SIRT7 requires its catalytic activity, suggesting that SIRT7 reduces MYC activity by acH3K18 deacetylation (Barber et al., 2012). In this context, one report indicates that SIRT7 protects against fatty liver formation in mice (Shin et al., 2013). This interplay between SIRT7 and MYC might suggest that SIRT7 functions as a tumor suppressor by inhibiting MYC activity, similar to SIRT6. However, a previous study demonstrated that hypoacetylation of H3K18 is associated with tumorigenesis and poor clinical outcome, and that SIRT7 is essential in maintaining low levels of acH3K18 in cancer cells (Barber et al., 2012). Further studies are needed to test whether SIRT7 might function as a tumor suppressor in some contexts.

Concluding remarks

Overall, studies have shown that there is a multi-faceted interplay between mammalian sirtuin proteins and the MYC and HIF transcription factor families (Table 1 and Fig. 3), potentially rendering some of the sirtuins attractive therapeutic targets to reverse metabolic reprogramming in cancer cells. Whereas the preponderance of the evidence suggests that SIRT1 in many contexts promotes cancer metabolism by working in conjunction with HIF and MYC family proteins, SIRT3, SIRT4 and SIRT6 all inhibit distinct aspects of the metabolic alterations observed in tumor cells. SIRT3 inhibits HIF activity by maintaining low cellular ROS levels; SIRT4 blocks MYC-mediated glutamine metabolism by inhibiting GDH; and SIRT6 attenuates transcriptional activity of HIF1 and MYC via effects on chromatin.

Cellular transformation generally requires both inactivation of tumor suppressor genes and increased activity of proto-oncogenes (Sherr, 2004). The absence of SIRT6 in immortalized mouse embryonic fibroblasts is sufficient to confer upon them tumorigenic potential (Sebastián et al., 2012). Thus, in this cellular context, SIRT6, by regulating HIF1 and/or MYC, qualifies as a tumor suppressor. Activation of SIRT6 in preformed cancers might conceivably represent a strategy to inhibit signaling through these oncogenic transcription factors. However, it is currently unknown whether elevated SIRT6 activity confers increased tumor suppression capacity. One report found that overexpression of SIRT6 induces apoptosis in diverse cancer cell types, but not in normal cells, although this effect was dependent on the mono-ADP-ribosyltransferase activity of SIRT6, likely implying that SIRT6-induced apoptosis represents a function of SIRT6 distinct from its metabolic roles (Van Meter et al., 2011). Similarly, SIRT6 overexpression in vivo seems to provide some protection against lung cancers in mice (Kanfi et al., 2012; Lombard and Miller, 2012).

Although we have focused on functions of SIRT6 in regulating MYC and HIF, it is very likely that other roles of SIRT6 are also relevant for its tumor suppressor capacity. As previously noted, SIRT6 promotes maintenance of genomic stability via multiple mechanisms. In addition, SIRT6 represses the activities of the lipogenic transcription factors SREBP1 and SREBP2 (Elhanati et al., 2013; Tao et al., 2013). Because an uninterrupted supply of lipids is crucial for tumor growth, maintenance of SREBP activity is likely important for the rapid proliferation of cancer cells, a hypothesis that has been confirmed in the context of a subset of gliomas (Guo et al., 2011). The role of SIRT6 in co-repressing JUN and consequently suppressing IIS is also likely relevant in this context (Sundaresan et al., 2012). JUN is itself a proto-oncogene, and increased IIS occurs in many diverse tumor types (Wong et al., 2010).

However, other data point to a Janus-faced role of SIRT6 in neoplasia. Elevated SIRT6 levels have been reported in pancreatic (Bauer et al., 2012), breast (Khongkow et al., 2013) and prostate (Liu et al., 2013b) carcinomas where SIRT6 contributes to cell migration, enhanced cell viability and chemotherapeutic resistance. Thus, SIRT6 can assume an oncogenic role in some contexts. In the setting of normal cells, SIRT6 might provide protection against transformation by suppressing metabolic reprogramming and maintaining genomic integrity. However, in some tumor types, SIRT6 function might be recruited to promote stress resistance, i.e. against genomic insult or other forms of cellular injury (Jedrusik-Bode et al., 2013; Miteva and Cristea, 2014; Simeoni et al., 2013). Given the pleiotropic nature of SIRT6’s roles in the cell, it is likely that additional major functions of this protein exist in normal and transformed cells that remain to be identified. Clearly, further studies are needed to clarify the opposing roles of SIRT6 in cancer, and to investigate the therapeutic potential of SIRT6 in established tumors.

Acknowledgements

We thank William Giblin and the anonymous reviewers for helpful comments on the manuscript, and apologize to those whose work was not cited due to space constraints.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

Eloise Mikkonen from the University of Tampere, Finland, is part of a collaborative project investigating a connection between herpes simplex virus and Alzheimer’s disease. Thanks to a Travelling Fellowship from DMM, she visited her collaborators in Umeå University, Sweden, and the team have now published their work in DMM. Read more on her story here.

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